Kaposi sarcoma (KS) is a potentially life threatening consequence of immunosuppression in patients that are infected with human herpes virus-8 (HHV-8). Most KS occurs in patients with acquired immunodeficiency syndrome (AIDS). Current KS therapies have limited efficacy and serious off target toxicities. Navidea has been developing 99mTc-tilmanocept(r), a wholly synthetic molecular construct that binds with very high affinity and specificity to the macrophage mannose receptor (CD206). The first commercial application for 99mTc-tilmanocept is as an intraoperative lymphatic mapping (ILM) agent for identifying sentinel lymph nodes (SLNs) during cancer surgeries to remove solid tumors. After a broad range of preclinical studies and highly successful clinical trials, the FDA and European regulators approved 99mTc-tilmanocept for ILM and identification of SLNs. Navidea has learned that KS tumor cells and also tumor associated macrophages (TAMs) in most types of cancer highly express CD206. In this grant application, Navidea is seeking support to evaluate a tilmanocept-like drug delivery construct (MT1001), which is intended to deliver doxorubicin to CD206 expressing cells. Doxorubicin is an important therapy for KS in AIDS patients, but its efficacy is limited due primarily to its off target cardiotoxicity. Heart muscle cells do not expres CD206. The central concept of this proposal is that MT1001 could concentrate doxorubicin in CD206 expressing cells, such as KS cells and their TAMs, while sequestering away this cardiotoxic drug from other tissues and especially from heart muscles. This would enhance the effectiveness of the drug while reducing or virtually eliminating its cardiotoxicity. An important feature of CD206's interactions with its ligands is that after CD206 ligand binding, the complex is internalized into endosomes inside the cell. Endosomes become acidified causing CD206 to release its ligand, allowing CD206 to recycle to the cell surface. Navidea has developing acid labile linkers, which are part of MT1001. These will permit MT1001 to release its doxorubicin payload only once they are in the endosomes of the targeted cells. Navidea's has shown that a MT1001-like prototype molecule specifically kills CD206 expressing cells. It also kills KS cells and their TAMs in KS biopsy explants maintained in culture, while sparing cells that do not express CD206. This Fast Track SBIR application requests support to complete a series of in vitro, cell culture based and preclinical animal studies to evaluate the likely safety and efficacy of MT1001 for the treatment of KS. The information from these studies will be combined with other information concerning chemical manufacturing controls (CMC) and synthesis optimization in an investigational new drug (IND) application that will be submitted to the FDA requesting permission to begin testing MT1001 in human KS patients. We anticipate that this project will bring an effective and life-sparing new therapy to KS patients who are in desperate need for such a new treatment. We also believe that given the data to date, this project will be a powerful gateway to a new class of anti-TAM therapies directed at solid tumors generally.